The main objective of this proposal is to analyze the functions of three genes that have been shown or to have been proposed as causes of retinal degenerative diseases. Preliminary studies indicate that products of these genes are not directly involved in phototransduction but may participate in the membrane/protein trafficking that are the basis of photoreceptor outer segment renewal, an essential but poorly understood process in photoreceptor cell biology. Specific hypotheses have been put forward regarding the physiological functions of each of these proteins, linking them to membrane vesicle budding, specificity of vesicle translocation, or an active transport function across the connecting cilium, respectively. A deficit in any of these functions should severely impact photoreceptor function and viability, and therefore will be a cause of retinal degeneration. Experimental approaches will be emphasize on a combination of in vivo analyses of animal models, in vitro biochemical characterizations, and a dissection of the molecular pathways through a search for interacting proteins. These studies are likely to generate new insight into the process of photoreceptor membrane renewal at the molecular level. It is our view that following the elucidation of the phototransduction cascade, many of the remaining genes which are involved in retinal degeneration but are not yet understood, may encode essential functions in the process of photoreceptor membrane renewal. Therefore the proposed studies should be of major importance to photoreceptor disease.